System and method for irradiation therapy using voxel based functional measurements of organs at risk

ABSTRACT

A method and apparatus for irradiation therapy using voxel based function measurements of organs-at-risk (OAR). The method includes determining size and location of each voxel of a plurality of voxels in a reference frame of a radiation device. The method further includes obtaining measurements that relate to utility of tissue type at each voxel. The method further includes determining a subset of the voxels that enclose an organ-at-risk (OAR) volume. The method further includes determining a value of a utility measure fj at each voxel of the subset based on a corresponding value of the measurements. The method further includes determining a series of beam shapes and intensities which minimize a value of an objective function that is based on a computed dose delivered to an OAR voxel multiplied by the utility measure fj for that voxel summed over all voxels.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of Provisional Appln. 62/029,590, filedJul. 28, 2014, the entire contents of which are hereby incorporated byreference as if fully set forth herein, under 35 U.S.C. §119(e).

BACKGROUND

Radiotherapy is a treatment for cancer patients involving the use ofhigh-energy radiation. When high-energy radiation is delivered to asubject, it kills cells in the body. Although the high-energy radiationkills tumor cells in the subject's body, it may also kill normal tissuecells and tissue cells of an organ-at-risk (OAR) that surround thetumor. Thus, the goal of conventional radiotherapy is to deliver asufficient radiation dose to the tumor to kill the tumor cells whileminimizing the radiation dose delivered to the normal tissue cells andOAR tissue cells that surround the tumor.

SUMMARY

It is here recognized that conventional methods for irradiation therapyare deficient, since all volume within the OAR is weighted equally andthus equal sparing is given to all volume within the OAR from theradiation dose. As a result, OAR function heterogeneity is notconsidered within the volume, which introduces a risk of distributinghigh radiation doses to OAR regions corresponding to high organfunction. This can result in higher normal tissue toxicity or fatalradiation-induced complications.

In a first set of embodiments, a method is provided for irradiationtherapy using voxel based functional measurements of organs-at-risk(OAR). The method includes determining size and location of each voxelof a plurality of voxels in a reference frame of a radiation device thatemits a beam of radiation with controlled intensity and beam crosssectional shape. The method further includes obtaining, on a processor,first measurements that relate to tissue type inside a subject at eachvoxel of the plurality of voxels based on a first imaging device. Themethod further includes obtaining, on a processor, different secondmeasurements that relate to utility of tissue type inside the subject ateach voxel of the plurality of voxels based on a second imaging device.The method further includes determining a first subset of the pluralityof voxels that enclose a target volume to be irradiated with atherapeutic dose of radiation by the radiation device. The methodfurther includes determining a second subset of the plurality of voxelsthat enclose an organ-at-risk (OAR) volume. The method further includesdetermining, on the processor, a value of a utility measure j at eachvoxel of the second subset based on a corresponding value of the secondmeasurements. The method further includes determining, on the processor,a series of beam shapes and intensities from the radiation device whichminimize a value of an objective function that is based on a computeddose delivered to an OAR voxel multiplied by the utility measure j forthat voxel summed over all voxels. The method further includescontrolling the radiation device to deliver the series of beam shapesand intensities.

In a second set of embodiments, a computer-readable medium carrying oneor more sequences of instructions is provided, where execution of theone or more sequences of instructions by one or more processors causesthe one or more processors to perform the step of receiving firstmeasurements from a first imaging device that relate to tissue typeinside a subject at each voxel of a plurality of voxels. Additionally,execution of the one or more sequences of instructions further causesthe processor to perform the step of receiving different secondmeasurements from a second imaging device that relate to utility oftissue type inside the subject at each voxel of the plurality of voxels.Additionally, execution of the one or more sequences of instructionsfurther causes the processor to perform the step of determining a valueof a utility measure j at each voxel of a subset of the plurality ofvoxels that enclose an organ-at-risk (OAR) volume inside the subjectbased on a corresponding value of the second measurements. Additionally,execution of the one or more sequences of instructions further causesthe processor to perform the step of determining a series of beam shapesand intensities from a radiation device which minimize a value of anobjective function that is based on a computed dose delivered to an OARvoxel multiplied by the utility measure j for that voxel summed over allvoxels. Additionally, execution of the one or more sequences ofinstructions further causes the processor to perform the step ofcontrolling the radiation device to deliver the series of beam shapesand intensities.

In a third set of embodiments, a system is provided for irradiationtherapy using voxel based functional measurements of organs-at-risk(OAR). The system includes a radiation device to emit a beam ofradiation with controlled intensity and beam cross sectional shape ineach voxel of a plurality of voxels in a reference frame of theradiation device. The system further includes one or more imagingdevices to obtain one or more measurements that relate to tissue typeinside a subject at each voxel of the plurality of voxels. The systemfurther includes at least one processor and at least one memoryincluding one or more sequence of instructions. The memory and thesequence of instructions are configured to, with the processor, causethe processor to receive the one or more measurements from the one ormore imaging devices; to determine a value of a utility measure f_(j) ateach voxel of a subset of the plurality of voxels that enclose anorgan-at-risk (OAR) volume inside the subject based on a correspondingvalue of the one or more measurements; to determine the controlledintensity and beam cross sectional shape in each voxel that minimize avalue of an objective function that is based on a computed dosedelivered to an OAR voxel multiplied by the utility measure f_(j) forthat voxel summed over all voxels and to control the radiation device todeliver the series of beam shapes and intensities.

Still other aspects, features, and advantages are readily apparent fromthe following detailed description, simply by illustrating a number ofparticular embodiments and implementations, including the best modecontemplated for carrying out the invention. Other embodiments are alsocapable of other and different features and advantages, and its severaldetails can be modified in various obvious respects, all withoutdeparting from the spirit and scope of the invention. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments are illustrated by way of example, and not by way oflimitation, in the figures of the accompanying drawings in which likereference numerals refer to similar elements and in which:

FIG. 1A is a block diagram that illustrates an example system forirradiation therapy using voxel based functional measurements oforgans-at-risk (OAR), according to an embodiment;

FIG. 1B is a block diagram that illustrates scan elements in a 2D scan,such as one scanned image from a CT scanner;

FIG. 1C is a block diagram that illustrates a plurality of voxels withina fixed frame of reference of the radiation source of FIG. 1A;

FIG. 2A is an image that illustrates an example of a scanned image toidentify tissue type in a subject, such as a scanned image from a CTscanner, according to an embodiment;

FIG. 2B is an image that illustrates the example scanned image of FIG.2A, where an example target area and OAR have been identified, accordingto an embodiment;

FIG. 2C is an image that illustrates the scanned image of FIG. 2A, withexample contour lines of radiation dose levels, based on a conventionalradiotherapy plan;

FIG. 3A is an image that illustrates an example scanned image toidentify example utility of a tissue type in a first subject, where anexample area of high utility has been identified, according to anembodiment;

FIG. 3B is an image that illustrates an example scanned image toidentify example utility of a tissue type in a second subject, accordingto an embodiment;

FIG. 3C is an image that illustrates an example scanned image toidentify example utility of a tissue type in a third subject, accordingto an embodiment;

FIG. 4 is a block diagram that illustrates an example OAR and exampletarget material in an example frame of reference of the exampleradiation source of FIG. 1A, according to an embodiment;

FIG. 5 is a flow diagram that illustrates an example of a method forirradiation therapy using voxel based functional measurements oforgans-at-risk (OAR), according to an embodiment;

FIG. 6A is a graph that illustrates an example of a displacement of anOAR from a nominal position over a movement phase, according to anembodiment;

FIG. 6B is a graph that illustrates an example of a probability curvethat the OAR will remain within a range of the nominal position, basedon the displacement curve of FIG. 6A;

FIG. 6C is a graph that illustrates an example of curves that providerespective low probability, average probability and high probabilitythat the OAR will remain within a range of the nominal position, overmultiple movement phases, according to an embodiment;

FIG. 7 is a block diagram that illustrates an example of a planningtarget volume that encloses the target material, according to anembodiment;

FIG. 8A is a graph that illustrates an example of a histogram of utilitymeasurements at each OAR voxel of the first subject OAR in FIG. 3A and apair of example curves based on the utility measurements at each OARvoxel, according to an embodiment;

FIG. 8B is a graph that illustrates an example of a histogram of utilitymeasurements at each OAR voxel of the second subject OAR in FIG. 3B anda pair of example curves based on the utility measurements at each OARvoxel, according to an embodiment;

FIG. 8C is a graph that illustrates an example of a histogram of utilitymeasurements at each OAR voxel of the third subject OAR in FIG. 3C and apair of example curves based on the utility measurements at each OARvoxel, according to an embodiment;

FIG. 9A is an image that illustrates the example scanned image of FIG.2C and identifies multiple example contour lines of radiation doselevels based on a conventional radiotherapy plan;

FIG. 9B is an image that illustrates the example scanned image of FIG.2B and identifies example contour lines of radiation dose levels,according to an embodiment;

FIG. 10A illustrates an example of a dose-volume histogram (DVH) of theconventional plan and the plan according to an embodiment forirradiation therapy;

FIG. 10B illustrates an example of a functional dose-volume histogram(fDVH) of the conventional plan and the plan according to an embodimentfor irradiation therapy;

FIG. 11 is a bar chart that illustrates examples of percentages of theOAR voxels receiving various radiation dosages and an example of the OARaverage radiation dosage in the conventional plan and plan according toan embodiment for irradiation therapy;

FIG. 12 is a block diagram that illustrates a computer system upon whichan embodiment of the invention may be implemented; and

FIG. 13 is a block diagram that illustrates a chip set upon which anembodiment of the invention may be implemented.

DETAILED DESCRIPTION

A method and apparatus are described for irradiation therapy using voxelbased functional measurements of organs-at-risk (OAR). In the followingdescription, for the purposes of explanation, numerous specific detailsare set forth in order to provide a thorough understanding of thepresent invention. It will be apparent, however, to one skilled in theart that the present invention may be practiced without these specificdetails. In other instances, well-known structures and devices are shownin block diagram form in order to avoid unnecessarily obscuring thepresent invention.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope are approximations, the numerical values set forth inspecific non-limiting examples are reported as precisely as possible.Any numerical value, however, inherently contains certain errorsnecessarily resulting from the standard deviation found in theirrespective testing measurements at the time of this writing.Furthermore, unless otherwise clear from the context, a numerical valuepresented herein has an implied precision given by the least significantdigit. Thus a value 1.1 implies a value from 1.05 to 1.15. The term“about” is used to indicate a broader range centered on the given value,and unless otherwise clear from the context implies a broader rangearound the least significant digit, such as “about 1.1” implies a rangefrom 1.0 to 1.2. If the least significant digit is unclear, then theterm “about” implies a factor of two, e.g., “about X” implies a value inthe range from 0.5X to 2X, for example, about 100 implies a value in arange from 50 to 200. Moreover, all ranges disclosed herein are to beunderstood to encompass any and all sub-ranges subsumed therein. Forexample, a range of “less than 10” can include any and all sub-rangesbetween (and including) the minimum value of zero and the maximum valueof 10, that is, any and all sub-ranges having a minimum value of equalto or greater than zero and a maximum value of equal to or less than 10,e.g., 1 to 4.

Some embodiments of the invention are described below in the context ofirradiation therapy for a mass in or near an OAR, such as a lung.However, the invention is not limited to this context. In otherembodiments other target materials and organs are involved as the OAR.For example, target tumor metabolism and hypoxia are applicable to theinvention. Additionally, in other examples, other OARs such as thebrain, liver, kidney and neck are applicable to the invention.

1. Overview

FIG. 1A is a block diagram that illustrates an example system 100 forirradiation therapy using voxel based functional measurements oforgans-at-risk (OAR), according to an embodiment. For purposes ofillustration, a living subject 190 is depicted, but is not part of thesystem 100. One or more imaging systems 121 are provided, to scan imagesof the subject 190 within an imaging systems volume 124 that encompassespart of the subject 190. In an example embodiment, the volume 124 mayencompass the entire subject 190. The imaging systems 121 arenon-invasive and obtain cross-sectional images that are axially stackedto generate imaging data of the volume 124. In an example embodiment,the imaging system 121 is a first imaging device that obtains firstmeasurements that relate to tissue type inside the volume 124. Forexample, the first imaging device is an X-ray Computed tomography (CT)scanner or a nuclear magnetic resonance imagery (MRI) scanner. In anexample embodiment, the imaging system 121 includes a second imagingdevice that obtains second measurements that relate to utility of tissuetype inside the volume 124. For example, the second imaging device is apositron emission tomography (PET) scanner, a Single photon emissioncomputed tomography (SPECT) scanner, a functional magnetic resonanceimager (fMRI) or a four-dimensional computed tomography (4DCT)-basedventilation/perfusion imaging system. The imaging systems 121 can beoperated at different times, to generate different measurements of thetissue type inside the volume 124.

As illustrated in FIG. 1A, a target material 192 indicated by a triangleis positioned within the subject 190. In an example embodiment, thetarget material 192 includes tumor cells. During movement phases of thesubject 190, such as during a breathing phase or heartbeats, the targetmaterial 192 shifts from a nominal position to a secondary positionindicated by the triangle with the broken line. Thus, at any giveninstance in time, the actual position of the target material 192 may notbe the nominal position. FIG. 1A depicts the movement of target material192 between the nominal position (solid line) and secondary position(dashed line). Additionally, a pair of OARs 194 is positioned within thesubject 190. The region of the volume 124 that is not occupied by thetarget material 192 or the OAR 194 is occupied by tissues in a categorycalled normal tissue.

As illustrated in FIG. 1A, the system 100 includes a radiation source170 that emits a beam 172 that penetrates the volume 124 over aplurality of volume elements or voxels 122 that are defined within aframe of reference of the radiation source 170. The radiation source 170transmits the beam 172 to each voxel 122 along the beam with anintensity and shape that is dependent on how many of each voxel 122along the beam is occupied by the target material 192, the OAR 194 ornormal tissue. Combining the effects of multiple beams (theirintensities and shapes), the goal is to transmit high dose to the targetmaterial 192, and low dose to the normal tissue and the OAR 194. Aprobability function is used to account for the movement phases of thesubject 190, and whether the classification of the target material 192,the OAR 194 or normal tissue for each voxel 122 along the beam willchange at various movement phases of the subject 190.

During the operation of the system 100, the radiation source 170 rotatesaround the subject 190, so that the beam 172 is directed at the targetmaterial 192 from multiple directions. At some angular positions of theradiation source 170, the beam 172 needs to pass through the OAR 194 toget to the target material 192. As illustrated in FIG. 1A, when theradiation source 170 rotates to a left side of the target material 192,the beam 172 needs to pass through the OAR 194 to get to the targetmaterial 192. However, at other angular positions of the radiationsource 170, the beam 172 need not pass through the OAR 194 to get to thetarget material 192. As illustrated in FIG. 1A, when the radiationsource 170 rotates to a top side of the target material 192, the beam172 need not pass through the OAR 194 to get to the target material 192.

As illustrated in FIG. 1A, a computer system 150 is provided to controlthe one or more imaging systems 121, to collect imaging data from theone or more imaging systems 121, to determine the intensity and shape ofthe beam 172 delivered to each voxel 122 in the volume 124 and totransmit the intensity and shape of the beam 172 for multiple beams tothe radiation source 170. The computer system 150 includes a functionbased radiation control process 140 to perform one or more steps of amethod described below with reference to FIG. 5. In various embodiments,the computer system 150 comprises one or more general purpose computersystems, as depicted in FIG. 12 or one or more chip sets as depicted inFIG. 13, and instructions to cause the computer or chip set to performone or more steps of a method described below with reference to FIG. 5.

FIG. 1B is a block diagram that illustrates scan elements in a 2D scan110, such as one scanned image of the volume 124 from the imaging system121, such as a CT scanner. The two dimensions of the scan 110 arerepresented by the x direction arrow 102 and the y direction arrow 104.The scan 110 consists of a two dimensional array of 2D scan elements(pixels) 112 each with an associated position. Typically, a 2D scanelement position is given by a row number in the x direction and acolumn number in the y direction of a rectangular array of scanelements. A value at each scan element position represents a measured orcomputed intensity or amplitude that represents a physical property(e.g., X-ray absorption, or resonance frequency of an MRI scanner) at acorresponding position in at least a portion of the spatial arrangementof the living body. The measured property is called amplitudehereinafter and is treated as a scalar quantity. In some embodiments,two or more properties are measured together at a pixel location andmultiple amplitudes are obtained that can be collected into a vectorquantity, such as spectral amplitudes in MRSI. Although a particularnumber and arrangement of equal sized circular scan elements 112 areshown for purposes of illustration, in other embodiments, more elementsin the same or different arrangement with the same or different sizesand shapes are included in a 2D scan.

FIG. 1C is a block diagram that illustrates the plurality of voxels 122that are defined in the volume 124 within a fixed frame of reference ofthe radiation source 170 of FIG. 1A. The fixed frame of reference of theradiation source 170 is defined based on the x-direction 102,y-direction 104 and z-direction 106. Thus, in an example embodiment, aparticular voxel 122 within the volume 124 in the frame of reference ofthe radiation source 170 is assigned a unique x-value, y-value andz-value. As previously discussed, some of the voxels 122 are occupied bytarget material 192, some of the voxels 122 are occupied by OAR material194 and the remaining voxels 122 in the volume 124 are occupied bynormal tissue. The computer system 150 determines the respectiveintensity and shape of the beam 172. Although a particular number andarrangement of equal voxel 122 are shown for purposes of illustration,in other embodiments, more voxels 122 in the same or differentarrangement with the same or different sizes and shapes are included inthe frame of reference of the radiation source 170. In an exampleembodiment, the voxel 122 has a length in a range of 3-5 millimeters, awidth in a range of 3-5 millimeters and a depth in a range of 2-3millimeters.

FIG. 2A is a block diagram that illustrates a scanned image 202 toidentify tissue type in the subject 190 from one of the imaging systems121, such as a CT scanner. As illustrated in the scanned image 202, aleft lung 210 and right lung 212 tissue types (dark) can be identifiedand differentiated from non-lung tissue types (light gray and white) inthe image 202. FIG. 2B is a block diagram that illustrates a scannedimage 204 to identify tissue type in the subject 190 that is similar tothe scanned image 202, where a target area 218 and a spinal cord 216(OAR) have been identified. In an example embodiment, an oncologistmarked the target area 218 of a tumor and the spinal cord 216, duringthe development of a conventional radiotherapy treatment plan. Duringconventional radiotherapy, a treatment plan is developed, whichmaximizes the radiation dose delivered to the target area 218, whileminimizing the radiation dose delivered to the OARs including the lungs210, 212 and spinal cord 216.

FIG. 2C is a block diagram that illustrates a scanned image 206 toidentify tissue type in the subject 190 that is similar to the scannedimage 204 and includes contour lines 222 of radiation dose levels, basedon the conventional radiotherapy plan. As illustrated in FIG. 2C,contour lines 222 of high radiation dose encircle the target area 218,indicating that the target area 218 receives a high radiation dose, tokill the tumor cells in the target area 218. Additionally, asillustrated in FIG. 2C, contour lines 220 of decreasing radiation doseare provided at increasing distance from the target area 218, to sparethe OARs including the lungs 210, 212 and spinal cord 216 from highradiation doses. As illustrated in FIG. 2C, the high radiation dosecontour lines are shaped to avoid the OAR (spinal cord 216), in order tospare the OAR from high radiation. During the computation of thetreatment plan for conventional radiotherapy, all OAR voxels are giventhe same weight, when minimizing the radiation dose delivered to theOAR. As further illustrated in FIG. 2C, in computing the treatment plan,at least part of the lung 210 is exposed to a radiation dose, asindicated by contour line 220, in order to cover all of the target area218 with a sufficient high radiation dose to kill the tumor cells.

FIG. 3A is a block diagram that illustrates a scanned image 302 toidentify utility of an OAR such as lungs 310, 312 in a first subject,where an area 314 of high utility has been identified. In an exampleembodiment, the scanned image 302 is generated with the imaging system121, such as a positron emission tomography (PET) scanner, a Singlephoton emission computed tomography (SPECT) scanner, a functionalmagnetic resonance imager (fMRI) or a four-dimensional computedtomography (4DCT)-based ventilation/perfusion imaging system. The image302 uses a gray scale, where white indicates a high utility area of thelungs 310, 312 and black indicates a low utility area of the lungs 310,312. During the development of a treatment plan for radiotherapy, itwould be advantageous to ensure that a lower radiation dose is deliveredto high utility areas of the OAR, including the area 314 depicted inFIG. 3A.

FIG. 3B is a block diagram that illustrates a scanned image 304 toidentify utility of an OAR such as lungs 330, 332 in a second subject.FIG. 3C is a block diagram that illustrates a scanned image 306 toidentify utility of an OAR such as lungs 340, 342 in a third subject. Bycomparing FIG. 3A-FIG. 3C, it is apparent that the utility of the lungsbetween the subjects varies considerably. For example, the area 314 ofhigh utility in the right lung 312 of the first subject (FIG. 3A) is notan area of high utility in the right lung 332 of the second subject(FIG. 3B). In another example, an area 334 of high utility in the leftlung 330 of the second subject (FIG. 3B) is not an area of high utilityin the left lung 310 of the first subject (FIG. 3A). During thedevelopment of a treatment plan for radiotherapy, it would be furtheradvantageous to consider the individualized utility of the OARs of eachsubject, so that the treatment plan is tailored for each subject.

FIG. 4 is a block diagram that illustrates a shape of a beam, an OARsuch as lungs 410, 420 and target material 430, 440 in a frame ofreference of the radiation source 170 of FIG. 1A, according to anembodiment. The frame of reference of the radiation source 170 includesan x-dimension 412 and a y-dimension 411. The radiation source 170 canirradiate a range 450 within the frame of reference, defined between x₁and x₂ in the x-dimension 412 and y₁ and y₂ in the y-dimension 411. Aplurality of rectangles (not shown) or multi-leaf collimators arepositioned in a head of the radiation source 170 and are selectivelypositioned to shape the beam 172 in one of a plurality of directions ata selective portion of the range 450 for one of multiple time intervals.As depicted in FIG. 4, the beam 172 is shaped at a portion 460 of thetarget material 440 in one of a plurality of directions for one ofmultiple time intervals. After the radiation source 170 is arranged sothat the beam 172 is shaped in one direction as depicted in FIG. 4, theradiation source 170 may transmit the beam 172 at selective intensitiesfor selective time intervals, before the radiation source 170 isreconfigured to shape the beam 172 in another direction to the targetmaterial 430, 440.

As further illustrated in FIG. 4, a first portion of the target material430 is on a near side of the radiation source 170 and thus the beam 172passes into the first portion of the target material 430 without passinginto the lung 410, and before passing into the lung 420 of the subject.However, a second portion of the target material 440 is positioned on afar side of the left lung 410 and thus the beam 172 needs to passthrough the left lung 410 in order to reach the second portion of thetarget material 440. Thus, when developing the treatment plan forradiotherapy, in order to ensure that the target material 430, 440receives a sufficient amount of high radiation dose to kill all tumorcells in the target material 430, 440, the lung 410 will necessarilyreceive some dose of radiation. It would be advantageous to ensure thatthe portions of the lung 410 which receive this dose of radiation arenot high utility areas such as area 314 in FIG. 3A, in order to preservethese high utility areas of the OAR. When the beam 172 is oriented atthe target material 430, 440 at a different direction than the directiondepicted in FIG. 4, the beam 172 may pass into the second portion of thetarget material 440 without needing to pass through the lung 410.

FIG. 5 is a flow diagram that illustrates an example of a method 500 forirradiation therapy using voxel based functional measurements oforgans-at-risk (OAR), according to an embodiment. For example, one ormore of the steps of method 500 are applied by process 140 of computersystem 150. Although the flow diagram of FIG. 5 is depicted as integralsteps in a particular order for purposes of illustration, in otherembodiments, one or more steps, or portions thereof, are performed in adifferent order, or overlapping in time, in series or in parallel, orare omitted, or one or more additional steps are added, or the method ischanged in some combination of ways.

After starting, in step 502, the plurality of voxels 122 are defined forthe subject 190 in the fixed reference frame for the radiation source170 for which the radiation beam 172 shape and intensity can becontrolled. As depicted in FIG. 1C, the voxels 122 are defined by thethree-dimensional axes 102, 104, 106 in the fixed reference frame of theradiation source 170. Additionally, the voxels 122 are positioned withinthe imaging systems volume 124 that encompasses a portion of the subject190, such that each voxel 122 is a respective volume element within thevolume 124. Additionally, as previously discussed, the intensity andshape of the beam 172 can be controlled by the computer system 150.

In step 504, tissue type measurements are obtained that indicate tissuetype for each voxel 122 in the volume 124. In an example embodiment, theimaging system 121 is a first imaging device that obtains the tissuemeasurements that relate to tissue type inside the volume 124. Forexample, the first imaging device is an X-ray Computed tomography (CT)scanner or a nuclear magnetic resonance imagery (MRI) scanner. Theobtained tissue measurements in step 504 are similar to the scannedimage 202 of FIG. 2A which indicate the target 218 tissue type as wellas different OAR tissue types, including lung 210, 212 tissue type andspinal cord 216 tissue type. In an example embodiment, the imagingsystem 121 obtains cross-sectional tissue type measurements that areaxially stacked and processed (including registration, interpolation andaveraging in various embodiments) to generate imaging of each voxel 122within the volume 124.

In step 506, utility measurements are obtained that indicate a level offunctional utility for each voxel 122 in the volume 124. In an exampleembodiment, the imaging system 121 is a second imaging device that isthe same as or different from the first imaging device and that obtainsmeasurements that relate to utility of tissue type inside the volume124. For example, the second imaging device is a positron emissiontomography (PET) scanner, a Single photon emission computed tomography(SPECT) scanner, a functional magnetic resonance imager (fMRI) or afour-dimensional computed tomography (4DCT)-based ventilation imagingsystem. The obtained utility measurements in step 506 are similar to thescanned images 302, 304, 306 of FIGS. 3A-3C which indicate the level offunctional utility the OAR in each subject. In an example embodiment,the imaging system 121 obtains cross-sectional utility measurements thatare axially stacked and processed (including registration, interpolationand averaging in various embodiments) to generate imaging of each voxel122 within the volume 124.

Imaging systems 121 are currently available to obtain ventilationutility measurements from the lungs. For example, ventilation utilitymeasurements can be obtained of the lungs using 4DCT, as described inMistry et al. Int J Radiat Oncol Biol Phys. 2013 87(4):825-31, which isincorporated by reference herein. Ventilation utility measurement canalso be obtained of the lungs using MRI, as described in Deninger et al.Magn. Reson. Med. 2002 48(2): 223-32, which is incorporated by referenceherein. Additionally, ventilation utility measurements can also beobtained of the lungs using SPECT, as described in Suga, Ann. Nucl. Med.2002 16(5): 303-10, which is incorporated by reference herein.

Imaging systems 121 are currently available to obtain perfusion utilitymeasurements for each OAR. For example, perfusion utility measurementscan be obtained of the OAR using CT, as described in Miles et al.Lancet. 1991 337(8742): 643-5, which is incorporated by referenceherein. Perfusion utility measurement can also be obtained of the OARusing SPECT, as described in Catafau, J Nucl. Med. 2001 42(2): 259-71,which is incorporated by reference herein. Additionally, perfusionutility measurements can also be obtained of the OAR using MRI, asdescribed in Berthezene et al. Radiology 1992 183: 667-72, which isincorporated by reference herein.

Imaging systems 121 are currently available to obtain neural utilitymeasurements for the OAR. For example, neural utility measurements canbe obtained of each OAR using fMRI, as described in Heeger and Ress,Nature Reviews Neuroscience 2002 3: 142-51, which is incorporated byreference herein. Imaging systems 121 are currently available to obtainutility measurements of tissue elasticity, stress and strain for theOAR. These utility measurements can be obtained of the OAR usingUltrasound, as described in Ophir et al. J Med. Ultrasonics 2002 29:155-71, which is incorporated by reference herein. Additionally, theseutility measurements can also be obtained of the OAR using MRI, asdescribed in Fowlkes et al. Med. Phys. 1995 22: 1771-8, which isincorporated by reference herein.

Imaging systems 121 are currently available to obtain diffusion utilitymeasurements for the OAR. For example, diffusion utility measurementscan be obtained of each OAR using MRI, as described in Padhani et al.Neoplasia 2009 11(2): 102-25, which is incorporated by reference herein.Imaging systems 121 are currently available to obtain utilitymeasurements of metabolic signatures for the OAR. These utilitymeasurements can be obtained of the OAR using MRI Spectroscopy, asdescribed in McKnight. Semin. Oncol. 2004 31(5): 605-17, which isincorporated by reference herein.

In step 508, motion measurements are obtained that indicate aprobability of change in tissue type at each voxel 122. As previouslydiscussed, the radiation source 170 transmits the beam 172 aiming todeliver high dose to voxels 122 in the beam that are occupied by thetarget material 192, transmits the beam 172 to deliver low dose tovoxels 122 in the beam that are occupied by the normal tissue andtransmits the beam 172 to deliver low dose to voxels 122 in the beamthat are occupied by the OAR 194. However, during movement phases of thesubject 190, such as during a breathing phase, the tissue classificationof each voxel 122 may change. A probability function is used to accountfor the movement phases of the subject 190, and whether theclassification of the target material 192, the OAR 194 or normal tissuefor each voxel 122 will change because of various movement phases of thesubject 190. FIG. 6A is a graph that illustrates an example of adisplacement 614 of an OAR from a nominal position over a movementphase, according to an embodiment. The horizontal axis 612 is timemeasured in units of seconds (s). The vertical axis 610 is displacementmeasured in units of centimeters (cm). In an example embodiment, thedisplacement 614 curve is generated with Varian® real-time positionmanagement (RPM).

FIG. 6B is a graph that illustrates an example of a probability curve654 that the OAR will remain within a range of the nominal position,based on the displacement 614 curve of FIG. 6A. The horizontal axis 652is displacement measured in units of centimeters (cm). The vertical axis650 is probability measured in a unitless ratio between 0 and 1. Forexample, if the voxel 122 is centered at the nominal position (0 cm) ofthe OAR, then the probability curve 654 indicates that the probabilitythat the OAR will move +0.4 cm during the movement phase of the subject190 is 20%.

As discussed above, the probability curve 654 of FIG. 6B is based on thesingle displacement 614 curve of the OAR depicted in FIG. 6A. Since eachmovement phase of the subject 190 is unique, a range of displacementcurves of the OAR can be generated based on a range of movement phasesof the subject 190. This range of displacement curves can then be usedto generate a range of probability curves. FIG. 6C is a graph thatillustrates an example of probability curves 670 that provide respectivelower bound 668 on the probability, average 665 of the probability andupper bound 664 on the probability that the OAR will remain within arange of the nominal position, over multiple movement phases of thesubject 190. The horizontal axis 662 is displacement measured in unitsof centimeters (cm). The vertical axis 660 is probability measured in aunitless ratio between 0 and 1. In other embodiments, the curves 666,670 and 664 are used in different ways.

In step 510, a set of target voxels are determined from the plurality ofvoxels 122 within the volume 124. This step is performed, using thetissue type measurements obtained in step 504 that indicate targettissue type in the volume 124. The set of target voxels are determined,to encompass the target material 192 that is positioned within thesubject 190. However, the set of target voxels is necessarily expandedbeyond the target material 192, to account for the uncertainty of thesubject 190. FIG. 7 is a block diagram that illustrates an example of aplanning target volume 702 that encloses the target material 792,according to an embodiment. As illustrated in FIG. 7, the planningtarget volume 702 encompasses the target volume 792 defined by initialimaging (solid line) and in the secondary position (dotted line)resulting from uncertainty. The planning target volume 702 is used todetermine the set of target voxels in step 510, to ensure that all ofthe target material 792 is within the set of target voxels, over alluncertainties. In some embodiments, the uncertainties arise from themovement of the subject 190. In other embodiments, the uncertaintiesarise from setup of one or more components of the system 100. In anexample embodiment, the planning target volume 702 is formed byexpanding the target material 192 by a margin in a range of 2 mm-1 cm.

In step 512, a set of OAR voxels are determined from the plurality ofvoxels 122 within the volume 124. This step is performed, using thetissue type measurements obtained in step 504 that indicate OAR tissuetype in the volume 124. The set of OAR voxels are determined, toencompass the one or more OARs 194 within the volume 124. The set of OARvoxels represent the OAR 194 inside the subject 190 to be irradiated theleast by the radiation source 170 for each of the one or more OARs 194.Those voxels 122 within the volume 124 that are not determined to betarget voxels in step 510 or OAR voxels in step 512 are determined to benormal tissue voxels.

In step 514, a utility measure f_(j) for each OAR voxel 122 isdetermined, based on the utility measurements at each OAR voxel obtainedin step 506. FIG. 8A is a graph that illustrates an example of ahistogram 814 of the utility measurements at each OAR voxel of thescanned image 302 of the first subject in FIG. 3A. The horizontal axis812 is a unitless ratio between 0 and 1 that indicates the utilitymeasurement of the OAR (as a fraction of ventilation change). In theexample embodiment where the OAR are lungs 310, 312 of the firstsubject, the fraction of ventilation change indicates the ratio ofventilation change of the lung voxel 122 over a breathing phase of thefirst subject and thus a higher fraction of ventilation change indicatesa higher utility measurement. The vertical axis 810 is a normalizedquantity of the lung voxels 122 at each utility measurement or fractionof ventilation change. FIG. 8B is a graph that illustrates an example ofa histogram 816 of utility measurements at each OAR voxel of the scannedimage 304 of the second subject in FIG. 3B. The horizontal axis 812 andvertical axis 810 are similar to those of FIG. 8A. FIG. 8C is a graphthat illustrates an example of a histogram 818 of utility measurementsat each OAR voxel of the scanned image 306 of the third subject in FIG.3C. The horizontal axis 812 and vertical axis 810 are similar to thoseof FIG. 8A.

In an example embodiment, the utility measure f_(j) for each OAR voxel122 is determined using a cumulative distribution of the utilitymeasurements. FIG. 8A illustrates a utility measure f_(j) curve 820 foreach OAR voxel 122 that is based on a cumulative distribution of theutility measurements in the histogram 814. The value of the curve 820 atany utility measurement (x) along the horizontal axis 812 is equal tothe collective area under the histogram 814 up to that utilitymeasurement (x). FIG. 8B illustrates a utility measure f_(j) curve 822for each OAR voxel 122 that is similarly based on a cumulativedistribution of the utility measurements in the histogram 816. FIG. 8Cillustrates a utility measure f_(j) curve 824 for each OAR voxel 122that is similarly based on a cumulative distribution of the utilitymeasurements in the histogram 818. In an example embodiment, the valueof the utility measure f_(j) for each OAR voxel 122 is used to determinea degree of minimization of the radiation dose for each OAR voxel 122.The utility measure f_(j) curves 820, 822, 824 have increasing valuesfor OAR voxels 122 for higher utility measurements, and thus theminimization of the radiation dose is enhanced for these OAR voxels 122with higher utility measurement.

In an example embodiment, the utility measure f_(j) for each OAR voxel122 is determined using a piecewise linear function of the utilitymeasurements. FIG. 8A illustrates a utility measure f_(j) piecewiselinear function 826 for each OAR voxel 122 including a first lineconnecting the origin to a peak of the histogram 814 and a secondhorizontal line equal to the peak value of the histogram 814 for thoseutility measurements greater than the utility measurement of the peak ofthe histogram 814. FIG. 8B illustrates a utility measure f_(j) piecewiselinear function 828 for each OAR voxel 122 that is similarly based on afirst line connecting the origin to a peak of the histogram 816 and asecond horizontal line equal to the peak value of the histogram 816 forthose utility measurements greater than the utility measurement of thepeak of the histogram 816. FIG. 8C illustrates a utility measure f_(j)piecewise linear function 830 for each OAR voxel 122 that is similarlybased on a first line connecting the origin to a peak of the histogram818 and a second horizontal line equal to the peak value of thehistogram 818 for those utility measurements greater than the utilitymeasurement of the peak of the histogram 818.

In an example embodiment, the value of the utility measure f_(j) foreach OAR voxel 122 is used to determine a degree of minimization of theradiation dose for each OAR voxel 122. Since the utility measure f_(j)piecewise linear functions 826, 828, 830 have a maximum value at thepeak value of the histograms, where a peak number of OAR voxels 122 havea particular utility measurement, the minimization of the radiation isenhanced for this peak number of OAR voxels 122. Additionally, since theutility measure f_(j) piecewise linear functions 826, 828, 830 has amaximum value for OAR voxels 122 with higher utility measurements, theminimization of the radiation dose is also enhanced for these OAR voxels122 with higher utility measurement. In other embodiments, j is definedbased on other functions of the utility measurements. In an exampleembodiment, the utility measure f_(j) can be based on any function thathas higher values for voxels with higher utility function, so that thedose delivered to those voxels is minimized. For example, the utilitymeasure f_(j) can be based on any monotonic increasing mathematicalfunction.

In step 516, a value of an objective function is determined based on asum of a computed radiation dose delivered to OAR voxels 122 weighted bythe utility measure f_(j) at the OAR voxels 122 and a computed dosedelivered to normal tissue voxels. The objective function can beexpressed as:

α^(OAR) ·f _(j) ·x _(j)+α^(NORMAL) ·y _(j)  (1)

where α^(OAR) and α^(NORMAL) are respective constants for the OAR voxelsand the normal tissue voxels. For example, a clinical planner couldchoose α^(OAR)=10 and α^(NORMAL)=2 based on their experience to generateradiotherapy plans. If more than one type of OAR is positioned withinthe volume 124, equation (1) includes a α^(OAR) term for each type ofOAR, where the α^(OAR) constant is scaled, depending on the type of OAR.In an example embodiment, if the OAR has a higher priority of sparing,then the α^(OAR) constant has a greater value, to enhance theminimization of the computed dose for that OAR. f_(j) is the utilitymeasure that was determined in step 514, j is the index of the j^(th)voxel 122 within the volume 124. x_(j) is the computed dose delivered tothe OAR voxels and y_(j) is the computed dose delivered to the normaltissue voxels. To perform step 516, for each voxel 122 in the volume124, if the voxel 122 encloses OAR tissue, then the computed dose x_(j)is multiplied by f_(j) and the α^(OAR) term. If the voxel 122 enclosesnormal tissue, then the computed dose y_(j) is just multiplied by theα^(NORMAL) term. These contributions are then summed for all voxels 122in the volume 124. As previously discussed in step 514, since theutility measure f_(j) has an increased value for OAR voxels 122 with ahigh utility measurement, the computed dose x_(j) in equation (1) willhave a higher priority of minimization for OAR voxels 122 with highutility measurements, as discussed in step 518 below.

In an example embodiment, an objective function can also be defined toinclude the computed dose delivered to the target tissue voxels withinthe volume 124, which can be expressed as:

α^(OAR) ·f _(j) ·x _(j)+α^(NORMAL) ·y _(j)+α^(TARGET)·(u _(z) +o_(z))  (2)

u _(z) =LB _(z) −z _(j) where LB _(z) >z _(j)  (3)

o _(z) =z _(j) −UB _(z) where UB _(z) <z _(j)  (4)

where z_(j) is the computed dose delivered to target voxels, LB_(z) isthe lower bound of a therapeutic dose to be delivered to the targetvoxels, UB_(z) is the upper bound of the therapeutic dose to bedelivered to the target voxels and α^(TARGET) is a constant for thetarget voxels. The term u_(z) represents an underdose to the targetvoxels, for those target voxels where LB_(z)>z_(j). An underdose to thetarget voxels is not desired, in order to kill all tumor cells in thetarget voxels. The term o_(z) represents an overdose to the targetvoxels, for those target voxels where z_(j)>UB_(z). An overdose to thetarget voxels is also not desired, as it reduces uniformity of the dosedelivered to the target voxels. Although equation (2) indicates that thesame constant α^(TARGET) is used for the overdose and underdose, theconstant α^(TARGET) is optional for either of the overdose andunderdose. Additionally, different constants may be used for theoverdose and underdose. Additionally, although equations (1) and (2)show the objective function in a linear formulation, this is merely oneexample in which the objective function can be written. In anotherembodiment, the objective function can be written in any formulation ofthe planning problem, such as a quadratic objective function.

In step 518, an irradiation plan is solved that minimizes the objectivefunction defined above in equation (1) or (2) subject to constraintsthat the total dosage at each voxel 122 is within certain lower andupper bounds for the tissue type associated with the voxel 122 and forone or more uncertainty scenarios caused by subject 190 movement phases.These constraints and uncertainty scenarios are expressed as:

x _(j)=Σ_(i) w _(i) ·D _(i,j,k) ·p(k) for jε0AR  (5)

y _(j)=Σ_(i) w _(i) ·D _(i,j,k) ·p(k) for jεN  (6)

z _(j)=Σ_(i) w _(i) ·D _(i,j,k) ·p(k) for jεT  (7)

LB _(x) <x<UB _(x)  (8)

LB _(y) <y<UB _(y)  (9)

LB _(z) <z _(j) <UB _(z)  (10)

where w_(i) is the weight for the beamlet directed at an i^(th)direction from the radiation source 170 to the j^(th) voxel, which aresolved for by minimizing the objective function, and D_(i,j,k) are dosematrices for the beamlet directed at the i^(th) direction to the j^(th)voxel under scenario k. The dose matrices are calculated beforehand asinput to the optimization, as discussed in Ref. Phys. Med Biol. 199944(11):R99; 155, Dose calculations from external photon beams inradiotherapy, Ahnnesio A. Aspradakis, M M, which is incorporated byreference herein. In step 518, for each voxel 122, the weight w_(i) foreach beamlet directed at the voxel 122 is determined, based on the valueof the utility measure f_(j) for that voxel 122.

In an example embodiment, for those voxels 122 of the OAR that have highutility, the value of the utility measure f_(j) is relatively high andthus the weight w_(i) of each beamlet directed at the voxel 122 will berelatively low, in order to minimize the overall termα^(OAR)*f_(j)*x_(j) in equation (1) for that voxel 122.

P(k) is the probability that the tissue type within each voxel 122 willremain unchanged over various uncertainty scenarios (k), such asbreathing of the subject 190. As previously discussed in step 508, theprobability curves are obtained based on one or more movement phases ofthe subject 190 and is used to determine the probability that the tissuetype within each voxel 122 will remain unchanged over the movementphases of the subject 190. In an example embodiment, in equation (2),the probability p(k) represents the probability that OAR tissue willremain within the voxel 122 over the movement phases of the subject 190,whereas in equation (3) the probability p(k) represents the probabilitythat normal tissue will remain within the voxel 122 over the movementphases of the subject 190.

The LB_(x) and UB_(x) are the respective lower bound and upper bound ofthe computed radiation dose x_(j) for the OAR voxels 122. The LB_(y) andUB_(y) are the respective lower bound and upper bound of the computedradiation dose y_(j) for the normal tissue voxels 122. As previouslydiscussed, the LB_(z) and UB_(z) are the respective lower bound andupper bound of the therapeutic radiation dose for the target voxels 122.The radiation dose delivered to the OAR voxels 122 is lower than theradiation dose delivered to the normal tissue voxels 122, which is inturn lower than the radiation dose delivered to the target voxels 122.Thus, the lower bound LB_(x) is less than the lower bound LB_(y) whichis less than the lower bound LB_(z). Similarly, the upper bound UB_(x)is less than the upper bound UB_(y), which is in turn lower than theupper bound UB_(z).

In step 520, the radiation source 170 is operated according to theirradiation plan solved in step 518. As depicted in FIG. 4, the shape ordirection of the beam 172 from the radiation source 170 is controlled ateach voxel 122 by selectively positioning rectangles at variouslocations within a head of the radiation source 170. The intensity ofthe beam 172 from the radiation source 170 is adjustable and may bedelivered to each voxel 122 at selective intensities over selective timeintervals. In an example embodiment, the control process 140 within thecomputer system 150 solves for the irradiation plan in step 518. In step520, the computer system 150 transmits signals to the radiation source170 according to the irradiation plan. In an example embodiment, thecomputer system 150 transmits signals to the radiation source 170 suchthat the intensity and shape of the beam 172 at each voxel 122 in theOAR 194 minimizes the radiation dose delivered to high utility regionsof the OAR 194.

2. Example Embodiments

FIG. 9A is a block diagram that illustrates a scanned image 902 that issimilar to the scanned image 206 of FIG. 2C. The scanned image 902identifies multiple contour lines 920 of radiation dose levels that weregenerated according to a conventional radiotherapy plan. As previouslydiscussed, the conventional radiotherapy plan provides equal weight toall regions of the lung 940 when determining the contour lines 920 forthe target region 930 and thus does not account for regions of differentutility measurement within the lung 940. The multiple contour lines 920within a high utility region 910 of the lung 940 include a highradiation dose of 49.5 Gray (Gy). FIG. 9B is a block diagram thatillustrates a scanned image 904 that identifies contour lines 950 ofradiation dose levels that are generated according to the irradiationplan of step 518. The contour lines 950 within the high utility region910 of the lung 940 has a reduced number of high radiation dose contourlines, relative to the contour lines 920 of FIG. 9A generated accordingto a conventional radiotherapy plan.

Specifically, the contour line corresponding to a high radiation dose of49.5 Gray (Gy) that is present within the high utility region 910 of thelung 940 in FIG. 9A has been shifted out of the high utility region 910in FIG. 9B, according to the irradiation plan of step 518. As a result,the high utility region 910 of the lung 940 is spared from this highradiation dose, due to the irradiation plan of step 518 which takes intoaccount utility measurements of the lung.

FIG. 10A illustrates an example of a dose-volume histogram (DVH) 1016 ofthe conventional plan and a DVH 1014 of the plan determined in step 518.The horizontal axis 1012 is the radiation dose in units of Gray (Gy).The vertical axis 1010 is a unitless fractional volume of the lungswhich have a minimum dosage of radiation, according to each plan. Forexample, the DVH 1016 indicates a fractional volume of 0.3 at a minimumdose of 20 Gy, which indicates that 30% of the lung volume has a dose of20 Gy or more, according to the conventional radiation plan. Based onFIG. 10A, a greater number of lung voxels 122 have a low dose (<15 Gy)in the irradiation plan determined in step 518 than the conventionalradiation plan. However, a reduced number of lung voxels 122 have a highdose (>15 Gy) in the irradiation plan determined in step 518 than theconventional radiation plan.

FIG. 10B illustrates an example of a functional dose-volume histogram(fDVH) 1066 of the conventional plan and a fDVH 1068 of the plandetermined in step 518. The horizontal axis 1012 is the radiation dosein units of Gray (Gy). The vertical axis 1050 is a unit lessutility-weighted fractional volume of the lungs, which is based on aproduct of the fractional volume of the lungs which has a minimum dosageof radiation, multiplied by the utility measure f_(j) of the voxels inthe fractional volume of the lungs, according to each plan. As depictedin FIGS. 8A-8C, the plan determined in step 518 involves increasedsparing of high utility regions of the lung from high radiation dosagethan the conventional radiotherapy plan which does not consider utilitymeasurements of the lung. Thus, in the fDVH 1066, 1068 of FIG. 10B,where lung voxels 122 of high utility are weighed more than voxels 122of low utility, the gap between the fDVH 1068 of the plan determined instep 518 and the fDVH 1066 of the conventional plan is even morepronounced for high dose (>15 Gy) than between the DVH 1014, 1016 ofFIG. 10A.

FIG. 11 is a bar chart that illustrates examples of percentages of theOAR voxels receiving various radiation dosages in the conventional planand plan according to an embodiment for irradiation therapy. The leftvertical axis 1110 is the fractional volume of the lungs which have aminimum dosage of radiation. As illustrated in FIG. 11, a fractionalvolume 1120 above 70% of the lungs had a minimum dosage of 5 Gy,according to the conventional plan, whereas a fractional volume 1122less than 70% of the lungs had the minimum dosage of 5 Gy, according tothe plan determined in step 518. As illustrated in FIG. 11, a fractionalvolume 1124 of approximately 50% of the lungs had a minimum dosage of 10Gy, according to the conventional plan, whereas a fractional volume 1126of approximately 45% of the lungs had the minimum dosage of 10 Gy,according to the plan determined in step 518. As illustrated in FIG. 11,a fractional volume 1128 of approximately 30% of the lungs had a minimumdosage of 20 Gy, according to the conventional plan, whereas afractional volume 1130 of approximately 20% of the lungs had the minimumdosage of 20 Gy, according to the plan determined in step 518. Asillustrated in FIG. 11, a fractional volume 1132 of approximately 15% ofthe lungs had a minimum dosage of 30 Gy, according to the conventionalplan, whereas a fractional volume 1134 of approximately 12% of the lungshad the minimum dosage of 20 Gy, according to the plan determined instep 518.

FIG. 11 is a bar chart that illustrates an example of the mean lung dose(MLD) in the conventional plan and plan according to an embodiment forirradiation therapy. The right vertical axis 1112 is a dosage of thelung in units of Gray (Gy). As illustrated in FIG. 11, a MLD 1136 of thelung voxels in the conventional plan is approximately 17.0 Gy, whereas aMLD 1138 of the lung voxels in the plan determined in step 518 isapproximately 14.0 Gy.

Thus, FIG. 11 shows that at each dose level the utility weighted planirradiates fewer high functioning lung pixels and thus a lower highfunctioning lung volume. The difference is statistically significant.

3. Hardware Overview

FIG. 12 is a block diagram that illustrates a computer system ˜00 uponwhich an embodiment of the invention may be implemented. Computer system˜00 includes a communication mechanism such as a bus 1210 for passinginformation between other internal and external components of thecomputer system 1200. Information is represented as physical signals ofa measurable phenomenon, typically electric voltages, but including, inother embodiments, such phenomena as magnetic, electromagnetic,pressure, chemical, molecular atomic and quantum interactions. Forexample, north and south magnetic fields, or a zero and non-zeroelectric voltage, represent two states (0, 1) of a binary digit (bit).).Other phenomena can represent digits of a higher base. A superpositionof multiple simultaneous quantum states before measurement represents aquantum bit (qubit). A sequence of one or more digits constitutesdigital data that is used to represent a number or code for a character.In some embodiments, information called analog data is represented by anear continuum of measurable values within a particular range. Computersystem 1200, or a portion thereof, constitutes a means for performingone or more steps of one or more methods described herein.

A sequence of binary digits constitutes digital data that is used torepresent a number or code for a character. A bus 1210 includes manyparallel conductors of information so that information is transferredquickly among devices coupled to the bus 1210. One or more processors1202 for processing information are coupled with the bus 1210. Aprocessor 1202 performs a set of operations on information. The set ofoperations include bringing information in from the bus 1210 and placinginformation on the bus 1210. The set of operations also typicallyinclude comparing two or more units of information, shifting positionsof units of information, and combining two or more units of information,such as by addition or multiplication. A sequence of operations to beexecuted by the processor 1202 constitutes computer instructions.

Computer system 1200 also includes a memory 1204 coupled to bus 1210.The memory 1204, such as a random access memory (RAM) or other dynamicstorage device, stores information including computer instructions.Dynamic memory allows information stored therein to be changed by thecomputer system 1200. RAM allows a unit of information stored at alocation called a memory address to be stored and retrievedindependently of information at neighboring addresses. The memory 1204is also used by the processor 1202 to store temporary values duringexecution of computer instructions. The computer system 1200 alsoincludes a read only memory (ROM) 1206 or other static storage devicecoupled to the bus 1210 for storing static information, includinginstructions, that is not changed by the computer system 1200. Alsocoupled to bus 1210 is a non-volatile (persistent) storage device 1208,such as a magnetic disk or optical disk, for storing information,including instructions, that persists even when the computer system 1200is turned off or otherwise loses power.

Information, including instructions, is provided to the bus 1210 for useby the processor from an external input device 1212, such as a keyboardcontaining alphanumeric keys operated by a human user, or a sensor. Asensor detects conditions in its vicinity and transforms thosedetections into signals compatible with the signals used to representinformation in computer system 1200. Other external devices coupled tobus 1210, used primarily for interacting with humans, include a displaydevice 1214, such as a cathode ray tube (CRT) or a liquid crystaldisplay (LCD), for presenting images, and a pointing device 1216, suchas a mouse or a trackball or cursor direction keys, for controlling aposition of a small cursor image presented on the display 1214 andissuing commands associated with graphical elements presented on thedisplay 1214.

In the illustrated embodiment, special purpose hardware, such as anapplication specific integrated circuit (IC) 1220, is coupled to bus1210. The special purpose hardware is configured to perform operationsnot performed by processor 1202 quickly enough for special purposes.Examples of application specific ICs include graphics accelerator cardsfor generating images for display 1214, cryptographic boards forencrypting and decrypting messages sent over a network, speechrecognition, and interfaces to special external devices, such as roboticarms and medical scanning equipment that repeatedly perform some complexsequence of operations that are more efficiently implemented inhardware.

Computer system 1200 also includes one or more instances of acommunications interface 1270 coupled to bus 1210. Communicationinterface 1270 provides a two-way communication coupling to a variety ofexternal devices that operate with their own processors, such asprinters, scanners and external disks. In general the coupling is with anetwork link 1278 that is connected to a local network 1280 to which avariety of external devices with their own processors are connected. Forexample, communication interface 1270 may be a parallel port or a serialport or a universal serial bus (USB) port on a personal computer. Insome embodiments, communications interface 1270 is an integratedservices digital network (ISDN) card or a digital subscriber line (DSL)card or a telephone modem that provides an information communicationconnection to a corresponding type of telephone line. In someembodiments, a communication interface 1270 is a cable modem thatconverts signals on bus 1210 into signals for a communication connectionover a coaxial cable or into optical signals for a communicationconnection over a fiber optic cable. As another example, communicationsinterface 1270 may be a local area network (LAN) card to provide a datacommunication connection to a compatible LAN, such as Ethernet. Wirelesslinks may also be implemented. Carrier waves, such as acoustic waves andelectromagnetic waves, including radio, optical and infrared wavestravel through space without wires or cables. Signals include man-madevariations in amplitude, frequency, phase, polarization or otherphysical properties of carrier waves. For wireless links, thecommunications interface 1270 sends and receives electrical, acoustic orelectromagnetic signals, including infrared and optical signals, thatcarry information streams, such as digital data.

The term computer-readable medium is used herein to refer to any mediumthat participates in providing information to processor 1202, includinginstructions for execution. Such a medium may take many forms,including, but not limited to, non-volatile media, volatile media andtransmission media. Non-volatile media include, for example, optical ormagnetic disks, such as storage device 1208. Volatile media include, forexample, dynamic memory 1204. Transmission media include, for example,coaxial cables, copper wire, fiber optic cables, and waves that travelthrough space without wires or cables, such as acoustic waves andelectromagnetic waves, including radio, optical and infrared waves. Theterm computer-readable storage medium is used herein to refer to anymedium that participates in providing information to processor 1202,except for transmission media.

Common forms of computer-readable media include, for example, a floppydisk, a flexible disk, a hard disk, a magnetic tape, or any othermagnetic medium, a compact disk ROM (CD-ROM), a digital video disk (DVD)or any other optical medium, punch cards, paper tape, or any otherphysical medium with patterns of holes, a RAM, a programmable ROM(PROM), an erasable PROM (EPROM), a FLASH-EPROM, or any other memorychip or cartridge, a carrier wave, or any other medium from which acomputer can read. The term non-transitory computer-readable storagemedium is used herein to refer to any medium that participates inproviding information to processor 1202, except for carrier waves andother signals.

Logic encoded in one or more tangible media includes one or both ofprocessor instructions on a computer-readable storage media and specialpurpose hardware, such as ASIC *1220.

Network link 1278 typically provides information communication throughone or more networks to other devices that use or process theinformation. For example, network link 1278 may provide a connectionthrough local network 1280 to a host computer 1282 or to equipment 1284operated by an Internet Service Provider (ISP). ISP equipment 1284 inturn provides data communication services through the public, world-widepacket-switching communication network of networks now commonly referredto as the Internet 1290. A computer called a server 1292 connected tothe Internet provides a service in response to information received overthe Internet. For example, server 1292 provides information representingvideo data for presentation at display 1214.

The invention is related to the use of computer system 1200 forimplementing the techniques described herein. According to oneembodiment of the invention, those techniques are performed by computersystem 1200 in response to processor 1202 executing one or moresequences of one or more instructions contained in memory 1204. Suchinstructions, also called software and program code, may be read intomemory 1204 from another computer-readable medium such as storage device1208. Execution of the sequences of instructions contained in memory1204 causes processor 1202 to perform the method steps described herein.In alternative embodiments, hardware, such as application specificintegrated circuit 1220, may be used in place of or in combination withsoftware to implement the invention. Thus, embodiments of the inventionare not limited to any specific combination of hardware and software.

The signals transmitted over network link 1278 and other networksthrough communications interface 1270, carry information to and fromcomputer system 1200. Computer system 1200 can send and receiveinformation, including program code, through the networks 1280, 1290among others, through network link 1278 and communications interface1270. In an example using the Internet 1290, a server 1292 transmitsprogram code for a particular application, requested by a message sentfrom computer 1200, through Internet 1290, ISP equipment 1284, localnetwork 1280 and communications interface 1270. The received code may beexecuted by processor 1202 as it is received, or may be stored instorage device 1208 or other non-volatile storage for later execution,or both. In this manner, computer system 1200 may obtain applicationprogram code in the form of a signal on a carrier wave.

Various forms of computer readable media may be involved in carrying oneor more sequence of instructions or data or both to processor 1202 forexecution. For example, instructions and data may initially be carriedon a magnetic disk of a remote computer such as host 1282. The remotecomputer loads the instructions and data into its dynamic memory andsends the instructions and data over a telephone line using a modem. Amodem local to the computer system 1200 receives the instructions anddata on a telephone line and uses an infra-red transmitter to convertthe instructions and data to a signal on an infra-red a carrier waveserving as the network link 1278. An infrared detector serving ascommunications interface 1270 receives the instructions and data carriedin the infrared signal and places information representing theinstructions and data onto bus 1210. Bus 1210 carries the information tomemory 1204 from which processor 1202 retrieves and executes theinstructions using some of the data sent with the instructions. Theinstructions and data received in memory 1204 may optionally be storedon storage device 1208, either before or after execution by theprocessor 1202.

FIG. 13 illustrates a chip set 1300 upon which an embodiment of theinvention may be implemented. Chip set 1300 is programmed to perform oneor more steps of a method described herein and includes, for instance,the processor and memory components described with respect to FIG. *12incorporated in one or more physical packages (e.g., chips). By way ofexample, a physical package includes an arrangement of one or morematerials, components, and/or wires on a structural assembly (e.g., abaseboard) to provide one or more characteristics such as physicalstrength, conservation of size, and/or limitation of electricalinteraction. It is contemplated that in certain embodiments the chip setcan be implemented in a single chip. Chip set 1300, or a portionthereof, constitutes a means for performing one or more steps of amethod described herein.

In one embodiment, the chip set 1300 includes a communication mechanismsuch as a bus 1301 for passing information among the components of thechip set 1300. A processor 1303 has connectivity to the bus 1301 toexecute instructions and process information stored in, for example, amemory 1305. The processor 1303 may include one or more processing coreswith each core configured to perform independently. A multi-coreprocessor enables multiprocessing within a single physical package.Examples of a multi-core processor include two, four, eight, or greaternumbers of processing cores. Alternatively or in addition, the processor1303 may include one or more microprocessors configured in tandem viathe bus 1301 to enable independent execution of instructions,pipelining, and multithreading. The processor 1303 may also beaccompanied with one or more specialized components to perform certainprocessing functions and tasks such as one or more digital signalprocessors (DSP) 1307, or one or more application-specific integratedcircuits (ASIC) 1309. A DSP 1307 typically is configured to processreal-world signals (e.g., sound) in real time independently of theprocessor 1303. Similarly, an ASIC 1309 can be configured to performedspecialized functions not easily performed by a general purposedprocessor. Other specialized components to aid in performing theinventive functions described herein include one or more fieldprogrammable gate arrays (FPGA) (not shown), one or more controllers(not shown), or one or more other special-purpose computer chips.

The processor 1303 and accompanying components have connectivity to thememory 1305 via the bus 1301. The memory 1305 includes both dynamicmemory (e.g., RAM, magnetic disk, writable optical disk, etc.) andstatic memory (e.g., ROM, CD-ROM, etc.) for storing executableinstructions that when executed perform one or more steps of a methoddescribed herein. The memory 1305 also stores the data associated withor generated by the execution of one or more steps of the methodsdescribed herein.

In the foregoing specification, the invention has been described withreference to specific embodiments thereof. It will, however, be evidentthat various modifications and changes may be made thereto withoutdeparting from the broader spirit and scope of the invention. Thespecification and drawings are, accordingly, to be regarded in anillustrative rather than a restrictive sense. Throughout thisspecification and the claims, unless the context requires otherwise, theword “comprise” and its variations, such as “comprises” and“comprising,” will be understood to imply the inclusion of a stateditem, element or step or group of items, elements or steps but not theexclusion of any other item, element or step or group of items, elementsor steps. Furthermore, the indefinite article “a” or “an” is meant toindicate one or more of the item, element or step modified by thearticle. As used herein, unless otherwise clear from the context, avalue is “about” another value if it is within a factor of two (twice orhalf) of the other value. While example ranges are given, unlessotherwise clear from the context, any contained ranges are also intendedin various embodiments. Thus, a range from 0 to 10 includes the range 1to 4 in some embodiments.

What is claimed is:
 1. A method comprising: determining size andlocation of each voxel of a plurality of voxels in a reference frame ofa radiation device that emits a beam of radiation with controlledintensity and beam cross sectional shape obtaining first measurementsthat relate to tissue type inside a subject at each voxel of theplurality of voxels based on a first imaging device; obtaining differentsecond measurements that relate to utility of tissue type inside thesubject at each voxel of the plurality of voxels based on a secondimaging device; determining a first subset of the plurality of voxels,wherein the first subset encloses a target volume to be irradiated witha therapeutic dose of radiation by the radiation device; determining asecond subset of the plurality of voxels, wherein the second subsetencloses an organ-at-risk (OAR) volume; determining on a processor avalue of a utility measure j at each voxel of the second subset based onthe a corresponding value of the second measurements determining on aprocessor a series of beam shapes and intensities from the radiationdevice which minimize a value of an objective function that is based ona computed dose delivered to an OAR voxel multiplied by the utilitymeasure j for that voxel summed over all voxels; and controlling theradiation device to deliver the series of beam shapes and intensities.2. A method as recited in claim 1 wherein the first imaging device isone of an X-ray Computed tomography (CT) scanner or an nuclear magneticresonance imagery (MRI) scanner.
 3. A method as recited in claim 1wherein the second imaging device is one of a positron emissiontomography (PET) scanner, a Single photon emission computed tomography(SPECT) scanner, a functional magnetic resonance imager (fMRI) or afour-dimensional computed tomography (4DCT)-based ventilation imagingsystem.
 4. A method as recited in claim 1 wherein the utility measuref_(j) is based on a piecewise linear cumulative distribution of thesecond measurements.
 5. A method as recited in claim 4 wherein thepiecewise linear cumulative distribution of the second measurementsincludes a constant maximum values of j for values of the secondmeasurements above a peak in a histogram of the values of the secondmeasurements.
 6. A method as recited in claim 1 wherein the OAR is alung within the subject.
 7. A method as recited in claim 1 wherein eachvoxel has a length in a range of 3-5 millimeters, a width in a range of3-5 millimeters and a depth in a range of 2-3 millimeters.
 8. A methodas recited in claim 1 wherein each voxel associated with a tissue typealso has an associated probability based on expected movement of thetissue type out of the voxel during the irradiation therapy.
 9. Acomputer-readable medium carrying one or more sequences of instructions,wherein execution of the one or more sequences of instructions by one ormore processors causes the one or more processors to perform the stepsof: receiving first measurements from a first imaging device that relateto tissue type inside a subject at each voxel of a plurality of voxels;receiving different second measurements from a second imaging devicethat relate to utility of tissue type inside the subject at each voxelof the plurality of voxels; determining a value of a utility measure jat each voxel of a subset of the plurality of voxels that enclose anorgan-at-risk (OAR) volume inside the subject based on a correspondingvalue of the second measurements; determining a series of beam shapesand intensities from a radiation device which minimize a value of anobjective function that is based on a computed dose delivered to an OARvoxel multiplied by the utility measure j for that voxel summed over allvoxels; and controlling the radiation device to deliver the series ofbeam shapes and intensities.
 10. A system comprising: a radiation deviceto emit a beam of radiation with controlled intensity and beam crosssectional shape in each voxel of a plurality of voxels in a referenceframe of the radiation device; one or more imaging devices to obtain oneor more measurements that relate to tissue type inside a subject at eachvoxel of the plurality of voxels; at least one processor; and at leastone memory including one or more sequence of instructions; the at leastone memory and the one or more sequence of instructions configured to,with the at least one processor, cause the at least one processor toreceive the one or more measurements from the one or more imagingdevices, to determine a value of a utility measure f_(j) at each voxelof a subset of the plurality of voxels that enclose an organ-at-risk(OAR) volume inside the subject based on a corresponding value of theone or more measurements, to determine the controlled intensity and beamcross sectional shape in each voxel that minimize a value of anobjective function that is based on a computed dose delivered to an OARvoxel multiplied by the utility measure f_(j) for that voxel summed overall voxels and to control the radiation device to deliver the series ofbeam shapes and intensities.
 11. A system as recited in claim 10 whereinthe imaging device is one of an X-ray Computed tomography (CT) scanneror an nuclear magnetic resonance imagery (MRI) scanner.
 12. A system asrecited in claim 10 wherein the imaging device is one of a positronemission tomography (PET) scanner, a Single photon emission computedtomography (SPECT) scanner, a functional magnetic resonance imager(fMRI) or a four-dimensional computed tomography (4DCT)-basedventilation imaging system.
 13. A system as recited in claim 10 whereinthe utility measure f_(j) is based on a piecewise linear cumulativedistribution of the measurements.
 14. A system as recited in claim 13wherein the piecewise linear cumulative distribution of the secondmeasurements includes a constant maximum values of j for values of thesecond measurements above a peak in a histogram of the values of thesecond measurements.
 15. A system as recited in claim 10 wherein the OARis a lung within the subject.
 16. A system as recited in claim 10wherein each voxel has a length in a range of 3-5 millimeters, a widthin a range of 3-5 millimeters and a depth in a range of 2-3 millimeters.